1. Field of the Invention
This invention relates to water-soluble camptothecin compounds. More particularly, the invention relates to esters of camptothecin compounds prepared by esterifying the hydroxyl group at the 20-position of camptothecin compounds to form nontoxic water-soluble prodrugs.
2. Discussion of the Background
Camptothecin is an optically active (20S) alkaloid isolated from the Campototheca acuminata tree which is native to China. The naturally occurring compound and many derivatives thereof exhibit anti-tumor activity. Camptothecin is a fused ring system having the structure shown below.
Major synthetic efforts have been directed to derivatizing the A-ring and/or the B-ring to improve cytotoxic activity and to improve water-solubility.
Camptothecin and camptothecin derivatives are cytotoxic compounds which can be used as chemotherapeutic agents. The cytotoxic activity of camptothecin compounds is believed to arise from the ability of these compounds to inhibit both DNA and RNA synthesis and to cause reversible fragmentation of DNA in mammalian cells. Camptothecin compounds inhibit the enzyme DNA topoisomerase I which is known to relax supercoiled DNA. This relaxation is brought about by breakage of one of the DNA strands in the formation of a covalent topoisomerase I-DNA complex. Camptothecin derivatives are believed to function by reversibly trapping the enzyme-DNA intermediate which is termed the "cleavable complex." Hsiang et al. (1989), Cancer Research, 49:4385-4389. The cleavable complex assay developed by Hsiang et al. is a standard test for determining the cytotoxic activity of camptothecin compounds.
Unfortunately, camptothecin and many camptothecin compounds are water insoluble. This water insolubility makes administration of camptothecin compounds difficult. Water soluble camptothecin derivatives have been prepared by derivatizing the A and B rings and by opening the lactone E-ring. See, for example, U.S. Pat. No. 4,981,968, U.S. Pat. No. 5,049,668 and EP 0 540,099. U.S. Pat. No. 4,914,205 discloses prodrug-type camptothecin compounds in which the lactone E-ring has been opened and modified to form an amide. U.S. Pat. No. 4,943,579 discloses camptothecin compounds in which the hydroxyl group at the 20-position is esterified to form camptothecin prodrugs which hydrolyze after injection to form the parent camptothecin compound.
A need continues to exist for new camptothecin compounds having high anti-tumor activity and yet low toxicity.